The expansion of available therapies, including options for individualization of therapy, represents an exciting space in the field of oncology. Cell-based therapies specifically have demonstrated efficacy in several disease settings, but in the case of solid tumors, the progress and promise of research has proceeded at a slower pace. We spoke with Catherine Handy Marshall, MD, MPH, to get her perspective on outlook for use of these therapies in patients with prostate cancer. Dr. Marshall is an Assistant Professor of Oncology in the Department of Oncology, Division of Genitourinary Cancer, at the Johns Hopkins University School of Medicine in Baltimore. Her work has been published in such journals as The New England Journal of Medicine, Future Oncology, and Prostate Cancer and Prostatic Diseases.
GU Oncology Now: The expansion of available therapies, including options for individualization of therapy, represents an exciting space in the field of oncology. Along with checkpoint inhibitor and cytokine inhibitor therapies, cell-based therapies—such as CAR-T and T-cell redirector therapies—have shown promise in patients with certain types of cancer, including melanoma, head and neck, lung, bladder, and kidney cancers. Yet immunotherapy has not been as successful in prostate cancer. Why is that? Is there something about the tumor microenvironment that makes prostate cancer more challenging to address with these treatments?
Catherine Handy Marshall, MD: The reasons are multi-factorial and include the tumor microenvironment. Some of the known biomarkers that predict response to immunotherapies that have been explored before— especially regarding checkpoint inhibitors—like tumor mutational load, are low in the majority of prostate cancers. Programmed death 1, or PD-1 expression is also low and there are few T-cell infiltrates in most prostate cancers.
Only about 2% of prostate cancers are mismatch repair deficient, another predictive biomarker for immunotherapy. Additionally, the tumor microenvironment does have immunosuppressive cell populations, so I think that all of these things contribute to why, within the drugs that have been approved so far to treat other cancers, we have not seen a lot of striking disease responses in prostate cancer.
Are there no cell-based therapies with a specific indication for prostate cancer that are approved right now?
The only immunotherapy drug that is approved for prostate cancer is sipuleucel-T, or Provenge®.It is an autologous cell-based therapy where patients have their own white blood cells taken out and activated outside of the body and reinfused back into them.
There are small subsets of patients who can get immunotherapy under US Food and Drug Administration (FDA) approvals. Pembrolizumab is approved under a tumor-agnostic – meaning regardless of the tissue of origin – – setting for patients with microsatellite instability (MSI)- high tumors, but fewer than about 5% of men with prostate cancer have an MSI-high type prostate cancer. However, if they do, then immunotherapy with checkpoint inhibitors would be approved for that indication. Pembrolizumab is also FDA approved for the treatment of cancers with a high tumor mutational burden—at least 10 mutations per megabase—would also be another FDA-approved indication. However, only a low percentage of men with prostate cancer would qualify for that.
Are there any clinical trials that are currently enrolling patients to explore cell-based therapies or other types of immunotherapy for prostate cancer?
There are many across the country. For patients and providers who are interested in enrolling in trials of immunotherapy for prostate cancer, it is important to consider enrollment any time a change of therapy is being considered. A lot of times, these clinical trials are testing in patients before chemotherapy, others are testing in patients after they have received chemotherapy, but what is important to consider is that the prior therapy or therapies are written into the exclusion and inclusion criteria for the studies. So, it is not necessary to wait until all other treatment options are exhausted to start looking at these trials.
There is often the problem in medicine where we have studies that are not inclusive of diverse ethnic populations and we are trying to extrapolate the results to everyone. Do you know if any of these trials are written to include a diverse population as part of the enrollment criteria?
Clinical trials should all be written to include a diverse population as part of the enrollment criteria. There are many barriers to enrolling diverse populations of people. One issue is the accessibility of trials and if they are being offered, another is the inclusion and exclusion criteria of trials, and another is the logistics of clinical trials and facilitating participation for diverse populations.
If there is a trial that would be a good fit for a particular patient, and the patient is interested, there may be resources, within the clinical trial site or even outside, like through the American Cancer Society, that can help with some of these barriers to clinical trial enrollment and participation. If there are trials in the area that you think might be a good fit, I would recommend reaching out to the trial team to see if they are able to help with other perceived barriers for patients. Clinical trials should be on the list of treatment options being considered for all patients who are changing therapies.
Today, so many individuals are conducting their own lay research and coming to the clinic asking their physicians to offer them certain treatments. How do you explain to them why, with their specific disease or comorbidities, cell-based therapies might not be effective for them?
Typically, patients come in with questions about immunotherapy in general, so I usually start with the types of treatment that they might have heard about – approved for prostate cancer and then those approved for other cancers. Most patients with advanced prostate cancer do not have the type of cancer that would be predicted to respond to treatment with FDA- approved immunotherapy. I use that as the lead-in to talk about clinical trials and options for clinical trials, and treatment strategies for how we think we might be able to help patients with prostate cancer. In general, other strategies that are being tested include combination treatments (ie immunotherapy + standard treatments in prostate cancer) or novel treatments that are being tested.
What are some of the combinations that might be considered?
People are looking at number of different combinations. Different combinations of checkpoint inhibitors, new targets for checkpoint inhibitors. For example, LAG-3 inhibitors, recently approved for use in melanoma, are being studied in prostate cancer. B7-H3 is another target being tested in prostate cancer. Cell based therapies – like PSMA CAR-T cells are being tested, BiTEs (bispecific T cell engagers) are being tested as well. Researchers are also looking at the use of radiation or cancer vaccines in combination with immunotherapy.
Some are looking at cytokine inhibitors, like inhibitors of interleukin-8 in combination with immunotherapy. Those are some of the newer ones that, again, are all under study. The side effects can really vary. One thing that is important to note, is that some of these trials require the patient to be in the hospital to receive the therapy. The range of potential toxicities from these treatments for patients with prostate cancer is very, very broad, from some that are likely to have minimal toxicities, to some that require being in the hospital to be monitored for the side effects.
The goal for all these treatments would be an improvement in overall survival, but there have been FDA-approved trials whose endpoint is metastasis-free survival, so it is likely that some will be tested, and maybe even more will be approved if they achieve that outcome.
What does the treatment horizon look like for the use of these therapies in patients with prostate cancer? Do you see the potential for some success in 5, 10, 20 years?
The pace of drug discovery and development in oncology is very rapid right now. So, this is a total guess, but I would say it is likely that along the line of 5 to 10 years, rather than 20 years, we might see more of these treatments start to work or that we discover some that work.
